Antibodies

Abstract

The present invention relates to antibodies binding to 5T4, including bispecific antibodies binding to 5T4 and CD3. The invention further provides pharmaceutical compositions comprising the antibodies and use of the antibodies for therapeutic and diagnostic procedures, in particular in cancer therapy.

The invention claimed is: 
     
       1. A bispecific antibody comprising a first heavy chain and a first light chain comprising a first antigen-binding region which binds to human 5T4, and a second heavy chain and a second light chain comprising a second antigen-binding region which binds to human CD3, wherein
 (a) the first antigen-binding region comprises a variable heavy chain (VH) region comprising the complementarity determining regions (CDRs) and the framework regions (FRs) within the amino acid sequence set forth in SEQ ID NO: 40 and a variable light chain (VL) region comprising the CDRs and FRs within the amino acid sequence set forth in SEQ ID NO: 44, and 
 (b) the second antigen-binding region comprises a VH region comprising the CDRs and FRs within the amino acid sequence set forth in SEQ ID NO: 68 and a VL region comprising the CDRs and FRs within the amino acid sequence set forth in SEQ ID NO: 60, and 
 wherein in each of the VH and VL regions, the CDRs and FRs are arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. 
 
     
     
       2. The bispecific antibody of  claim 1 , which comprises a human IgG1 Fc region. 
     
     
       3. The bispecific antibody of  claim 2 , wherein the Fc region is a human IgG1m(f) allotype. 
     
     
       4. The bispecific antibody of  claim 1 , which comprises a kappa light chain constant region and lambda light chain constant region. 
     
     
       5. The bispecific antibody of  claim 1 , wherein in both the first heavy chain and the second heavy chain, the amino acid residues at the positions corresponding to L234, L235, and D265 in a human IgG1 heavy chain according to EU numbering are F, E, and A, respectively. 
     
     
       6. The bispecific antibody according to  claim 1 , wherein the bispecific antibody comprises a human IgG1 Fc region, and wherein the first heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and F405 in a human IgG1 heavy chain according to EU numbering are F, E, A, and L, respectively, and the second heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and K409 in a human IgG1 heavy chain according to EU numbering are F, E, A, and R, respectively, and wherein the first light chain and second light chain comprise light chain constant regions comprising the amino acid sequences set forth in SEQ ID NOs: 95 and 96, respectively. 
     
     
       7. The bispecific antibody according to  claim 6 , wherein the first heavy chain comprises a constant region consisting of the amino acid sequence set forth in SEQ ID NO: 92, and the second heavy chain comprises a constant region consisting of the amino acid sequence set forth in SEQ ID NO: 93. 
     
     
       8. The bispecific antibody according to  claim 1 , wherein the bispecific antibody comprises a human IgG1 Fc region, and wherein the first heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and K409 in a human IgG1 heavy chain according to EU numbering are F, E, A, and R, respectively, and the second heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and F405 in a human IgG1 heavy chain according to EU numbering are F, E, A, and L, respectively, and wherein the first light chain and second light chain comprise light chain constant regions comprising the amino acid sequences set forth in SEQ ID NOs: 95 and 96, respectively. 
     
     
       9. The bispecific antibody according to  claim 8 , wherein the first heavy chain comprises a constant region consisting of the amino acid sequence set forth in SEQ ID NO: 93, and the second heavy chain comprises a constant region consisting of the amino acid sequence set forth in SEQ ID NO: 92. 
     
     
       10. The bispecific antibody of  claim 1 , which is a full-length antibody. 
     
     
       11. The bispecific antibody of  claim 1 , wherein the first heavy and light chains and the second heavy and light chains are all inter-connected by disulfide bonds. 
     
     
       12. A bispecific antibody comprising a first heavy chain and a first light chain comprising a first antigen-binding region which binds to human 5T4, and a second heavy chain and a second light chain comprising a second antigen-binding region which binds to human CD3, wherein
 (a) the first antigen-binding region comprises a variable heavy chain (VH) region comprising the complementarity determining regions (CDRs) and the framework regions (FRs) within the amino acid sequence set forth in SEQ ID NO: 40 and a variable light chain (VL) region comprising the CDRs and FRs within the amino acid sequence set forth in SEQ ID NO: 44, and 
 (b) the second antigen-binding region comprises a VH region comprising the CDRs and FRs within the amino acid sequence set forth in SEQ ID NO: 68 and a VL region comprising the CDRs and FRs within the amino acid sequence set forth in SEQ ID NO: 60, 
 wherein in each of the VH and VL regions, the CDRs and FRs are arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, 
 wherein the bispecific antibody comprises a human IgG1 Fc region, and wherein the first heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and K409 in a human IgG1 heavy chain according to EU numbering are F, E, A and R, respectively, and the second heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and F405 in a human IgG1 heavy chain according to EU numbering are F, E, A, and L, respectively, and 
 wherein the first light chain and second light chain comprise light chain constant regions consisting of the amino acid sequences set forth in SEQ ID NOs: 95 and 96, respectively. 
 
     
     
       13. A bispecific antibody comprising a first heavy chain and a first light chain comprising a first antigen-binding region which binds to human 5T4, and a second heavy chain and a second light chain comprising a second antigen-binding region which binds to human CD3, wherein
 (a) the first antigen-binding region comprises a variable heavy chain (VH) region consisting of the amino acid sequence set forth in SEQ ID NO: 40 and a variable light chain (VL) region consisting of the amino acid sequence set forth in SEQ ID NO: 44, and 
 (b) the second antigen-binding region comprises a VH region consisting of the amino acid sequence set forth in SEQ ID NO: 68 and a VL region consisting of the amino acid sequence set forth in SEQ ID NO: 60. 
 
     
     
       14. The bispecific antibody of  claim 13 , wherein the bispecific antibody comprises a human IgG1 Fc region. 
     
     
       15. The bispecific antibody of  claim 14 , wherein the Fc region is a human IgG1m(f) allotype. 
     
     
       16. The bispecific antibody of  claim 13 , which comprises a kappa light chain constant region and lambda light chain constant region. 
     
     
       17. The bispecific antibody of  claim 13 , wherein in both the first heavy chain and the second heavy chain, the amino acid residues at the positions corresponding to L234, L235, and D265 in a human IgG1 heavy chain according to EU numbering are F, E, and A, respectively. 
     
     
       18. The bispecific antibody according to  claim 13 , wherein the bispecific antibody comprises a human IgG1 Fc region, and wherein the first heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and F405 in a human IgG1 heavy chain according to EU numbering are F, E, A, and L, respectively, and the second heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and K409 in a human IgG1 heavy chain according to EU numbering are F, E, A, and R, respectively, and wherein the first light chain and second light chain comprise light chain constant regions comprising the amino acid sequences set forth in SEQ ID NOs: 95 and 96, respectively. 
     
     
       19. The bispecific antibody according to  claim 18 , wherein the first heavy chain comprises a constant region consisting of the amino acid sequence set forth in SEQ ID NO: 92, and the second heavy chain comprises a constant region consisting of the amino acid sequence set forth in SEQ ID NO: 93. 
     
     
       20. The bispecific antibody according to  claim 13 , wherein the bispecific antibody comprises a human IgG1 Fc region, wherein the first heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and K409 in a human IgG1 heavy chain according to EU numbering are F, E, A, and R, respectively, and the second heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and F405 in a human IgG1 heavy chain according to EU numbering are F, E, A, and L, respectively, and wherein the first light chain and second light chain comprise light chain constant regions comprising the amino acid sequences set forth in SEQ ID NOs: 95 and 96, respectively. 
     
     
       21. The bispecific antibody according to  claim 20 , wherein the first heavy chain comprises a constant region consisting of the amino acid sequence set forth in SEQ ID NO: 93, and the second heavy chain comprises a constant region consisting of the amino acid sequence set forth in SEQ ID NO: 92. 
     
     
       22. The bispecific antibody of  claim 13 , which is a full-length antibody. 
     
     
       23. The bispecific antibody according to  claim 13 , wherein the first heavy and light chains and the second heavy and light chains are all inter-connected by disulfide bonds. 
     
     
       24. A bispecific antibody comprising a first heavy chain and a first light chain comprising a first antigen-binding region which binds to human 5T4, and a second heavy chain and a second light chain comprising a second antigen-binding region which binds to human CD3, wherein
 (a) the first antigen-binding region comprises a variable heavy chain (VH) region consisting of the amino acid sequence set forth in SEQ ID NO: 40 and a variable light chain (VL) region consisting of the amino acid sequence set forth in SEQ ID NO: 44, and 
 (b) the second antigen-binding region comprises a VH region consisting of the amino acid sequence set forth in SEQ ID NO: 68 and a VL region consisting of the amino acid sequence set forth in SEQ ID NO: 60, 
 wherein the bispecific antibody comprises a human IgG1 Fc region, and wherein the first heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and K409 in a human IgG1 heavy chain according to EU numbering are F, E, A, and R, respectively, and the second heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265, and F405 in a human IgG1 heavy chain according to EU numbering are F, E, A, and L, respectively, and 
 wherein the first light chain and second light chain comprise light chain constant regions consisting of the amino acid sequences set forth in SEQ ID NOs: 95 and 96, respectively. 
 
     
     
       25. A composition comprising the bispecific antibody of  claim 1  and a carrier. 
     
     
       26. A composition comprising the bispecific antibody of  claim 13  and a carrier. 
     
     
       27. A composition comprising the bispecific antibody of  claim 24  and a carrier. 
     
     
       28. A kit comprising the bispecific antibody of  claim 1  and instructions for use. 
     
     
       29. A kit comprising the bispecific antibody of  claim 13  and instructions for use. 
     
     
       30. A kit comprising the bispecific antibody of  claim 24  and instructions for use.